Oxcarbazepine, a more tolerable alternative to the popular anticonvulsant drug carbamazepine, is used to treat epilepsy and has been proposed for use in the treatment of psychosomatic diseases and trigeminal neuralgia as described in U.S. Pat. No. 3,642,775. It has also been proposed for use in the treatment of Parkinsonian syndromes as described in U.S. Pat. No. 5,658,900, and AIDS-related neural disorders as described in WO 94/20110.
Several different routes for the preparation of oxcarbazepine are described in prior art documents such as: U.S. Pat. No. 3,642,775; U.S. Pat. No. 4,579,683; CA 1,112,241 and EP 028 028. In addition to being low yielding, these routes also hold the disadvantage of either starting with the costly raw material carbamazepine or they require the use of highly toxic reagents (i.e phosgene or cyanogen chloride) and are therefore impractical when transiting to commercial scale.
Processes better suited for large-scale production are claimed in U.S. Pat. No. 5,808,058 and U.S. Pat. No. 6,670,472. The process disclosed in U.S. Pat. No. 5,808,058 is depicted in Scheme 1. It begins with the carbamoylation of the readily available starting material 10-methoxyiminostilbene (10-methoxy-5H-dibenz[b,f]azepine) I, to give 10-methoxycarbamazepine II. This is achieved using an alkali metal cyanate like sodium cyanate and a relatively strong organic or inorganic acid, preferably acetic acid. The carbamoylation is then followed by hydrolysis of the enol-ether group under mildly acidic aqueous conditions to furnish oxcarbazepine III. Unfortunately, under the above carbamoylation conditions, a concomitant reaction, hydrolysis of the enol-ether group of 10-methoxyiminostilbene to the corresponding ketone, 5,11-dihydro-10H-dibenz[b,f]azepine-10-one (oximinostilbene) IV, also occurs. Once formed, IV will not undergo further conversion to oxcarbazepine in the presence of the metal cyanate and acid. Consequently, a mixture of products and related impurities are produced which requires a tedious and uneconomical purification procedure which results in low yields (45% to 65%) of final oxcarbazepine. Also, the purity of the final product is not reported.

An alternative process involving a condensation reaction with chlorosulfonyl isocyanate is disclosed in the same patent. As illustrated in Scheme 2, the enol-ether moiety of 10-methoxyiminostilbene I is first hydrolyzed in dilute acid to produce oximinostilbene IV, which is isolated and reacted with chlorosulfonyl isocyanate in a halogenated solvent to provide intermediate V. The chlorosulfonyl group of V is then hydrolyzed by the addition of water in the same pot to give oxcarbazepine III. There are drawbacks to this process. Firstly, the preparation of oximinostilbene IV requires harsh (reflux) conditions, and involves a tedious work-up procedure. Secondly, the reaction with chlorosulfonyl isocyanate and the subsequent hydrolysis also requires a relatively complicated isolation procedure giving a very low overall yield of only 34% oxcarbazepine. The purity of the final product is not reported.

U.S. Pat. No. 6,670,472 discloses a more efficient process derived from U.S. Pat. No. 5,808,058 which involves reacting 10-methoxyiminostilbene I with a metal cyanate in the presence of a weak, recyclable, organic acid (which contributes HOCN). Preferably the weak organic acid is benzoic acid, that is relatively insoluble in the solvent, preferably toluene. This results in an improved selectivity for the desired carbamoylation reaction relative to the hydrolysis of the enol-ether. This step is then followed by hydrolysis of the enol-ether group with a dilute acid, like hydrochloric acid, in a biphasic solvent system (preferably toluene/water) such that the product is insoluble in both phases but the impurities are soluble in at least one of the phases. The product is then isolated by filtration and purified once by recrystallization. Although this process offers some advantages, the yield is sacrificed, being only 49% even under optimized conditions.
The prior art processes described above, although better than those listed earlier, still suffer from serious drawbacks including complicated isolation procedures, inefficiency and/or low yields.
It is therefore an object of this invention to overcome the deficiencies of the prior art and provide a higher yielding, cost-effective, and scalable process for the commercial production of highly pure oxcarbazepine III.
It is a further object of this invention to provide a process where oxcarbazepine intermediate IV is made in a higher yielding, cost-effective, and scalable process for the commercial production.
Further objects will be realized by those skilled in the art from the following summary of the invention and detailed description of embodiments of the invention.